Tannate Compositions, Methods of Making and Methods of Use

ABSTRACT

Tannate compositions containing active pharmaceutical ingredients to be used for treating nausea, vomiting, pain, convulsions, and insomnia and manufacturing processes for preparing the tannate compositions.

This is a continuation-in-part of U.S. patent application Ser. No.10/921,438 filed on Aug. 19, 2004 which is a continuation of U.S. Pat.No. 6,869,618 which claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/282,969 filed Apr. 10, 2001; and U.S. patentapplication Ser. No. 10/269,027 filed Oct. 10, 2002 which claims thebenefit of U.S. Provisional Patent Application Ser. No. 60/328,990 filedOct. 12, 2001.

FIELD OF THE INVENTION

The invention relates to tannate compositions containing activepharmaceutical ingredients selected from the following therapeuticclasses: antinausea, antiemetic, antiinsomnia, analgesics andanticonvulsives. The invention also relates to methods of making theabove tannate compositions and methods of use.

BACKGROUND OF THE INVENTION

The use of tannate salts of active pharmaceutical ingredients is wellknown. U.S. Pat. No. 6,287,597 describes tannate products containingpyrilamine tannate and phenylephrine tannate. The January 1990 issue ofAnnals of Allergy, Volume 64, describes combinations of chlorpheniraminetannate, pyrilamine tannate and phenylephrine tannate. An article inClinical Medicine, dated September 1965, pages 1475-1478, describestablets of pyrilamine tannate, chlorpheniramine tannate and amphetaminetannate. Phenylephrine tannate compositions are disclosed in U.S. Pat.No. 5,599,846 and phenylephrine tannate and chlorpheniramine tannatecompositions are disclosed in U.S. Pat. No. 6,037,358. None of thesereferences describe the problems with tannate pharmaceutical productscaused by the large size of the tannate molecule. Because of its size,the percentage of active free base within the tannate salt issignificantly lower than that in other salt forms such as thehydrochloride or maleate. The presence of low active percentages and thevariable purity of the commercially available tannate salts leads to thestoichiometry of the active free base to tannic acid in the tannatesalts to vary from batch to batch. This problem was noted in U.S. Pat.Nos. 5,599,846 and 5,663,415. This causes significant processingproblems during manufacture and increases the likelihood thatcommercially available pharmaceutical products contain variable and insome instances, sub-therapeutic levels of the active drug substancescreating dosing problems. None of these references suggest or describepharmaceutical compositions containing tannate salts of activeingredients that are prepared with reduced variability in active drugcontent and increased certainty that the active drug is delivered withinthe therapeutic range. Also, none of the references suggest or describetannate pharmaceutical compositions in the therapeutic classes of activeingredients for antinausea, antiemetic, antiinsomnia, analgesics, oranticonvulsives.

None of the references discussed above suggest or describe theproduction of a tannate composition by means of an in-situ conversion ofthe active ingredient to the tannate salt in the presence of adispersing agent using the method described herein to provide a dosageform which affords a sustained release of the active ingredient overprolonged intervals of time. Since the prolonged drug release characterof the tannate salt enables the development of less frequent dosingregimens, such a composition is needed to improve patient compliancewith dosage requirements.

SUMMARY OF THE INVENTION

The present invention relates to therapeutic compositions forsymptomatic treatment of nausea, vomiting, insomnia, pain andconvulsions in a warm-blooded animal where that composition comprises apharmaceutically effective amount of an active pharmaceutical ingredientin each category as a tannate of consistent purity.

The present invention also relates to therapeutic compositionscomprising a pharmaceutically effective amount of representative activepharmaceutical ingredients as tannates for each of the above therapeuticcategories combined with non-tannate forms of the active pharmaceuticalingredient to provide both immediate and sustained releasecharacteristics in the same dosage form.

The above therapeutic compositions are incorporated into various dosageforms such as semi-solid dosage forms which include liquid suspensionsand soft gelatin capsules and solid dosage forms which include capsules,chewable tablets, and tablets.

The present invention also relates to a manufacturing process forin-situ conversion and incorporation thereof, of tannate salt complexesof antinausea, antiemetic, antiinsomnia, analgesic and anticonvulsiveclasses of pharmaceutical compounds into a sustained release therapeuticdosage form. By starting with a commonly available salt or free base ofthe active pharmaceutical ingredient, which is subsequently convertedand incorporated in-situ as a tannate salt complex, the inventionprovides an efficient and reproducible method of manufacture for bothsolid and liquid or semi-solid products containing active ingredienttannate salt complexes.

The manufacture of tannate liquid and semi-solid dosage forms isperformed according to processes described in U.S. Pat. No. 6,869,618and U.S. Pub. No. 2005/0202050, both references are incorporated hereinby reference.

The manufacture of tannate solid dosage forms is performed according toU.S. Pub. No. 2003/0077321 and U.S. Pub. No. 2005/0202080, bothreferences are incorporated herein by reference.

The present invention also relates to methods of administering apharmaceutically effective amount of active ingredient tannate complexof consistent purity to a warm-blooded animal.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel therapeutic compositioncontaining a tannate salt of active ingredients of consistent purityselected from the antinausea therapeutic class. A representative activeingredient is doxylamine prepared by a tannate conversion process whichincludes the steps of mixing the doxylamine as a salt or in the freebase form with tannic acid in a suitable solvent to generate a mixture.The mixing step is performed in the presence of a dispersing agent suchas magnesium aluminum sulfate either natural or synthetic, preferablysynthetic. The presence of the dispersing agent prevents the clumpingand aggregation of the tannate salt formed and promotes uniformity inthe mixture. Example 1, which is illustrative of a typical suspensionformulation of the present invention, is prepared as follows:

Example 1

Preparation of Doxylamine Tannate Suspension Amount Ingredient % W/V(Kg) Doxylamine Succinate 0.100% 1.7 Tannic Acid 0.325% 5.525*Neusilin ™, UFL2 0.800% 13.600 Xanthan Gum 0.350% 5.950 Sodium CitrateDehydrate 1.000% 17.000 Citric Acid 0.200% 3.4 Glycerin 20.000% 340.000Saccharin Sodium 0.400% 6.800 Methylparaben 0.200% 3.400 Sodium Benzoate0.100% 1.700 Sucrose 10.000% 170.000 Artificial Bubble Gum 1.100% 18.700Flavor PFC9861 FD&C Blue #1 0.010% 0.170 *= Based on 100% pure,anhydrous material

Purified water, 1200 kg, is added to a 500 gallon mixing vessel. Sodiumcitrate dihydrate and citric acid are added to the purified water andare mixed until dissolved. The neusilin and xanthan gum are added andthoroughly dispersed. Then the tannic acid is added and thoroughlydispersed. The doxylamine succinate is then added and mixing iscontinued for 20-30 minutes. The sucrose and saccharin sodium are addedand dispersed. The artificial bubble gum flavor and FD&C Blue #1 areadded and mixed for approximately 5 minutes. After adding and dispersingthe glycerin, methylparaben and sodium benzoate, the pH of theformulation is adjusted to within the range of 4.8-5.2 and thesuspension is diluted to a final volume of 1700 L and mixed for 30minutes.

Example 2

Preparation of Doxylamine Tannate Soft Gel Capsule Ingredient % In TotalW/V Amount (g) Doxylamine Succinate 26.67 400.00 Tannic Acid, USP 40.00600.00 Magnesium Aluminum Silicate 6.67 100.00 Lactose 20.0 300.00Purified Water, USP 6.67 100.00 Totals 100.00 1500.00

The tannic acid, doxylamine succinate, magnesium aluminum silicate andlactose powders were mixed for a period of 10 minutes in a planetarymixer to obtain a uniform blend. While continuing to mix, 150 mL ofpurified water was sprayed onto the dry powder blend. The conversionprocess occurred as soon as the tannic acid and API salts weremoistened. Mixing was continued for an additional 20 minutes. At thispoint, the conversion product had a dough-like consistency, but wasstill able to be poured from the bowl. The wet mass material wasincorporated into soft gelatin capsules using techniques known in theart.

A non-exclusive list of other antinausea therapeutic agents that can beused in the above Examples are: proclorperazine, promethazine HCl,metochlopromide HCl, trimethobenzamide HCl, and ondansetron HCl.

Example 3

Preparation of Promethazine Tannate Suspension Total weight Raw Material% in total Reqd. (g) Promethazine HCl, USP 0.50% 50.000 Tannic Acid, USP0.50% 50.000 Neusilin Grade UFL2 0.80% 80.0000 Sodium Citrate Dihydrate,USP 1.90% 190.0000 Aspartame 0.20% 20.0000 Acesulfame K 0.20% 20.0000Glycerin, USP 20.00% 2000.0000 Citric Acid, Anhydrous, USP 1.15%115.0000 Methylparaben, NF 0.20% 20.0000 Sodium Benzoate, NF 0.10%10.0000 Xanthan Gum 0.45% 45.0000 Strawberry Flavor 0.40% 40.0000 FD&CRed #40 0.040% 4.0000 Purified Water, USP 74.06% 7406.0000 Total 100.00%10000.0

Promethazine HCl is dissolved in purified water. In a stainless steelmixing tank, the neusilin and tannic acid are dispersed in water using asuitable stirrer. While stirring the neusilin/tannic acid dispersion inthe tank at low speed, the promethazine HCl solution is transferred insmall portions to the dispersion. Stirring is continued for a minimum of10 minutes.

In a separate mixing tank, the citric acid and sodium citrate aredissolved in purified water. The xanthan gum is slowly added and mixeduntil dispersed. The contents of the tank containing the activeingredient/tannic acid conversion are transferred to the xanthan gumsuspending medium and mixed for a period of 10-30 minutes. Thesweeteners, colors and flavors are subsequently added to the suspendingmedium with mixing. The sodium benzoate and methylparaben are dispersedin glycerin and subsequently added to the suspending medium and mixed toachieve a uniform dispersion. The pH is adjusted to pH 5 and purifiedwater is added to the required volume.

A non-exclusive list of other antiemetic therapeutic agents that can beused in the above Example are: cyclizine, diphenhydramine, meclizine,chlorpromazine, droperidol, hydroxyzine, metoclopramide,proclorperazine, and trimethobenzamide, cisapride, h2-receptorantagonists, and ondansetron.

Example 4

Preparation of Hydrocodone Tannate Tablet Dosage Form Raw Material % W/WTotal wt (kg) Hydrocodone Bitartrate 0.5 0.250 Tannic Acid, USP 0.50.250 Magnesium Aluminum Silicate, NF 8.12 4.060 Avicel PH 102 67.7633.880 Methocel E-10M 1.40 0.700 Corn Starch 0.80 0.400 Di-Pac 12.006.000 Sodium Saccharin 2.00 1.000 Calcium Phosphate Dibasic 2.80 1.400Xanthum Gum 3.00 1.500 Talc 0.56 0.280 Magnesium Stearate 0.56 0.280Purified Water N/A 8.5 L* Total 100.000% *Removed upon drying

Add the hydrocodone bitartrate, tannic acid, magnesium aluminumsilicate, avicel pH102 and methocel E-10M to a small paddle blender.While mixing the powders, spray with purified water. The material shouldexhibit a dough-like texture when complete. Add the remaining powdersand mix until uniform. If excess water is present, it may be removed bydrying prior to tabletting using conventional techniques.

A non-exclusive list of other analgesics that can be used in the aboveExample are: codeine, diacetylmorphine, dihydrocodeine, hydromorphone,meperidine, methadone, morphine, oxycodone, oxymorphone andpropoxyphene.

Example 5

Preparation of Diazepam Tannate Suspension Raw Material % W/V mg/5 mlDiazepam 0.100% 5 Tannic Acid 0.100% 5 Saccharin Sodium 0.300% 0.015Sucrose 10.000% 0.500 Glycerin 7.500% 0.375 Magnesium Aluminum Silicate0.800% 0.040 Xanthum gum 0.520% 0.026 Dibasic sodium phosphate 1.000%1.050 Methylparaben 0.200% 0.010 Sodium benzoate 0.100% 0.005 FD&C RedNo. 40 0.040% 0.002 Strawberry Flavor 0.500% 0.025 Purified Water qs tovolume N/A

The sodium phosphate dibasic is dissolved in purified water in asuitable stainless steel mixing tank. The MAS, followed by xanthan gum,is dispersed in the solution. The coloring agent FD&C Red No. 40 and theartificial strawberry flavor are then added and mixed to generate thesuspending medium. In a separate mixing tank, the MAS and tannic acidare dispersed in water using a suitable stirrer. Mixing is continueduntil a uniform dispersion is achieved.

Diazepam is dissolved in purified water. While stirring the MAS/tannicacid dispersion in the mixing tank at low speed, the diazepam solutionis transferred in small portions to the dispersion. Stirring iscontinued for a minimum of 10 minutes. After mixing, the contents of thetank are transferred to the suspending medium and mixed for a period of5 minutes.

The sodium benzoate and methylparaben are dispersed in glycerin in amixing tank using a suitable mixer. The glycerin mixture is then addedto the suspending medium and mixed to achieve a uniform dispersion.Finally, purified water is added to make up the suspension to therequired volume.

A non-exclusive list of other sedatives that can be used in the aboveExample are: clorazepate, estazolam, flurazepam, lorazepam, midazolam,nitrazepam, oxazepam, temazepam, triazolam, quazepam, zolpidem,zaleplon, amitriptyline, trimipramine, and trazodone.

Example 6

Preparation of Phenytoin Tannate Chewable Tablet Ingredient % W/V Amount(Kg) Phenytoin 10.00 4.840 Tannic Acid, USP 10.00 4.840 Neusilin 1.350.653 Mannitol 35.50 17.180 Sodium Saccharin 0.90 0.396 Corn Starch 0.900.446 Methocel E-10M 1.35 0.653 DiPac 48.83 21.500 Calcium PhosphateDibasic 2.70 1.188 Xanthan Gum 1.57 0.691 Artificial Strawberry Flavor0.90 0.396 FD&C Blue No. 1 0.09 0.040 Talc 0.45 0.198 Magnesium Stearate0.45 0.198 Purified Water NA NA

The tannic acid and neusilin powders are mixed in a blender for about 10minutes. The phenytoine is dissolved in water and sprayed onto thepowders while mixing. The mannitol and sodium saccharin are added andmixed until uniform. The methocel is added and mixed until uniform. Anaqueous solution of corn starch is then applied to the powders whilemixing.

After drying to remove the excess water, the material is milled. Themilled powder is then blended with the remaining ingredients dipac,calcium phosphate dibasic, xanthan gum, flavor, color, magnesiumstearate and talc until uniform and compressed into tablets usingtechniques known in the art.

A non-exclusive list of other anticonvulsion therapeutic agents that canbe used in the above Example are: hydantoins including mephenytoin;succimides including ethosuximide and methsuccimide; benzodiazepines,which are better known for their use as tranquilizers and sedatives,including clonazepam, clorazepate, diazepam, carbamazepine, valproicacid, gabapentin, topiramate, felbamate, and phenobarbital.

Example 7

Preparation of Dimenhydrinate Tannate and Dimenhydrinate Non-TannateTablet Dosage Form Ingredient % In Total, w/v Amount (g) Dimenhydrinate12.50% 1000.0 Tannic Acid, USP 12.50% 750.00 Magnesium Aluminum 2.00%176.00 Silicate (MAS), NF Methocel E-10M (HPMC) 35.88% 3157.42 Lactose32.53% 2602.58 FD&C Blue #1 Aluminum Lake 0.30% 24.00 Colloidal SiliconDioxide 0.50% 40.00 Magnesium Stearate, NF 1.25% 100.00 Purified Water,USP~* NA 150.00 TOTAL 100.00% 8000.0 *An excess of 10% is added to rawmaterials used in the wet granulation to correct for losses.

Tablets utilizing the above formulation are prepared as follows. Thetannic acid, MAS, and ¾ dimenhydrinate dry powders are mixed for aperiod of 10 minutes in a planetary mixer to obtain a uniform blend.While continuing to mix, 150 mL of purified water is sprayed onto thedry powder blend. The conversion process occurs as soon as the tannicacid and API salts are moistened. Mixing is continued for an additional20 minutes. At this point, the conversion product has a dough-likeconsistency, but is still able to be poured from the bowl.

To a separate mixing vessel, most preferably a paddle blender, thefollowing dry powders are added: methocel E-10M (HPMC) and lactose. Theconversion product is poured evenly over these dry powders, and themixture is then blended for 20 minutes. At this point, a productresembling a typical wet granulation is obtained. The mixture is thendried and milled as needed. The remainder of the excipients and thedimenhydrinate are added and the mixture is blended for an additional 20minutes. The final blend is then processed into tablets using techniqueswell known in the art.

Reasonable variations, such as those which would occur to a skilledartisan, can be made herein without departing from the scope of theinvention.

1. A therapeutic tannate complex composition for the symptomatic reliefof nausea in warm-blooded animals in need of such treatment, saidcomposition comprising a pharmaceutically effective amount of anantinausea agent, tannic acid, a dispersing agent and a pharmaceuticallyacceptable carrier.
 2. The therapeutic composition of claim 1, whereinthe antinausea agent is selected from the group consisting of:doxylamine, proclorperazine, promethazine HCl, metochlorpromide HCl,trimethobenzamide HCl, and ondansetron HCl.
 3. The therapeuticcomposition of claim 2, wherein the antinausea agent is doxylamine. 4.The therapeutic composition of claim 1 further comprising a non-tannateactive pharmaceutical ingredient.
 5. The therapeutic composition ofclaim 4 wherein the non-tannate active pharmaceutical ingredient is anantinausea agent selected from the group consisting of: doxylamine,proclorperazine, promethazine HCl, metochlopromide HCl,trimethobenzamide HCl, and ondansetron HCl.
 6. The therapeuticcomposition of claim 1 in solid dosage form.
 7. The therapeuticcomposition of claim 1 in semi-solid dosage form.
 8. A therapeutictannate complex composition for the symptomatic relief of vomiting inwarm-blooded animals in need of such treatment, said compositioncomprising a pharmaceutically effective amount of an antiemetic, tannicacid, a dispersing agent and a pharmaceutically acceptable carrier. 9.The therapeutic composition of claim 8, wherein the antiemetic isselected from the group consisting of: promethazine, cyclizine,diphenhydramine, meclizine, chlorpromazine, droperidol, hydroxyzine,metoclopramide, proclorperazine, and trimethobenzamide, cisapride,h2-receptor antagonists, and ondansetron.
 10. The therapeuticcomposition of claim 9, wherein the antiemetic is promethazine.
 11. Thetherapeutic composition of claim 8 further comprising a non-tannateactive pharmaceutical ingredient.
 12. The therapeutic composition ofclaim 11 wherein the non-tannate active pharmaceutical ingredient is anantiemetic selected from the group consisting of: promethazine,cyclizine, diphenhydramine, meclizine, chlorpromazine, droperidol,hydroxyzine, metoclopramide, proclorperazine, and trimethobenzamide,cisapride, h2-receptor antagonists, and ondansetron.
 13. The therapeuticcomposition of claim 8 in solid dosage form.
 14. The therapeuticcomposition of claim 8 in semi-solid dosage form.
 15. A therapeutictannate complex composition for the symptomatic relief of pain inwarm-blooded animals in need of such treatment, said compositioncomprising a pharmaceutically effective amount of an analgesic, tannicacid, a dispersing agent and a pharmaceutically acceptable carrier. 16.The therapeutic composition of claim 15, wherein the analgesic isselected from the group consisting of: codeine, diacetylmorphine,dihydrocodeine, hydrocodone, hydromorphone, meperidine, methadone,morphine, oxycodone, oxymorphone and propoxyphene.
 17. The therapeuticcomposition of claim 16, wherein the analgesic is hydrocodone.
 18. Thetherapeutic composition of claim 15 further comprising a non-tannateactive pharmaceutical ingredient.
 19. The therapeutic composition ofclaim 18 wherein the non-tannate active pharmaceutical ingredient is ananalgesic selected from the group consisting of: codeine,diacetylmorphine, dihydrocodeine, hydrocodone, hydromorphone,meperidine, methadone, morphine, oxycodone, oxymorphone andpropoxyphene.
 20. The therapeutic composition of claim 15 in soliddosage form.
 21. The therapeutic composition of claim 15 in semi-soliddosage form.
 22. A therapeutic composition for the symptomatic relief ofinsomnia in warm-blooded animals in need of such treatment, saidcomposition comprising a pharmaceutically effective amount of asedative, tannic acid, a dispersing agent and a pharmaceuticallyacceptable carrier.
 23. The therapeutic composition of claim 22, whereinthe sedative is selected from the group consisting of: clorazepate,diazepam, estazolam, flurazepam, lorazepam, midazolam, nitrazepam,oxazepam, temazepam, triazolam, quazepam, zolpidem, zaleplon,amitriptyline, trimipramine, and trazodone.
 24. The therapeuticcomposition of claim 23, wherein the sedative is diazepam.
 25. Thetherapeutic composition of claim 22 further comprising a non-tannateactive pharmaceutical ingredient.
 26. The therapeutic composition ofclaim 25 wherein the non-tannate active ingredient is a sedativeselected from the group consisting of: clorazepate, diazepam, estazolam,flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam,triazolam, quazepam, zolpidem, zaleplon, amitriptyline, trimipramine,and trazodone.
 27. The therapeutic composition of claim 22 in soliddosage form.
 28. The therapeutic composition of claim 22 in semi-soliddosage form.
 29. A therapeutic composition for the symptomatic relief ofconvulsions in warm-blooded animals in need of such treatment, saidcomposition comprising a pharmaceutically effective amount of ananticonvulsive, tannic acid, a dispersing agent and a pharmaceuticallyacceptable carrier.
 30. The therapeutic composition of claim 29, whereinthe anticonvulsive is selected from the group consisting of: phenytoine,mephenytoin, ethosuximide, methsuccimide, clonazepam, clorazepate anddiazepam, carbamazepine, valproic acid, gabapentin, topiramate,felbamate, and phenobarbital.
 31. The therapeutic composition of claim30, wherein the anticonvulsive is phenytoine.
 32. The therapeuticcomposition of claim 29 further comprising a non-tannate activepharmaceutical ingredient.
 33. The therapeutic composition of claim 32wherein the non-tannate pharmaceutical ingredient is an anticonvulsiveselected from the group consisting of: phenytoine, mephenytoin,ethosuximide, methsuccimide, clonazepam, clorazepate and diazepam,carbamazepine, valproic acid, gabapentin, topiramate, felbamate, andphenobarbital.
 34. The therapeutic composition of claim 29 in soliddosage form.
 35. The therapeutic composition of claim 29 in semi-soliddosage form.
 36. A process for the conversion of at least onepharmaceutical ingredient into a tannate salt complex for incorporationinto a therapeutic liquid or semi-solid dosage form, the processcomprising: (a) dissolving the salt or free base of the activepharmaceutical ingredient in a pharmaceutically acceptable liquid in thepresence of a dispersing agent and tannic acid under stirring, to form adispersion wherein the tannic acid component is of either a natural orsynthetic source; (b) combining the tannate salt complex of the activepharmaceutical ingredient without isolation or purification withpharmaceutically acceptable excipients to generate a therapeutic dosageform; wherein the active pharmaceutical ingredient is selected form thegroup consisting of an antinausea agent, an antiemetic, a sedative andan anticonvulsive and wherein the antinausea agent is selected from thegroup consisting of doxylamine, prochloroperazine, promethazine HCL,metochioropromide HCL and ondansetron HCL.
 37. The process according toclaim 36 wherein the dispersing agent provided in step (a) is selectedfrom the group consisting of natural magnesium aluminum silicate andsynthetic magnesium aluminum silicate.
 38. The process according toclaim 37 wherein the dispersing agent is synthetic magnesium aluminumsilicate.
 39. The process according to claim 36 wherein step (b)includes adding a non-tannate active pharmaceutical ingredient. 40.(canceled)
 41. (canceled)
 42. The process of claim 36 wherein theantiemetic is selected from the group consisting of: promethazine,cyclizine, diphenhydramine, meclizine, chlorpromazine, droperidol,hydroxyzine, metoclopramide, proclorperazine, and trimethobenzamide,cisapride, h2-receptor antagonists, and ondansetron.
 43. The process ofclaim 36 wherein the sedative is selected from the group consisting of:clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam,nitrazepam, oxazepam, temazepam, triazolam, quazepam, zolpidem,zaleplon, amitriptyline, trimipramine, and trazodone.
 44. (canceled) 45.The process of claim 36 wherein the anticonvulsive is selected from thegroup consisting of: phenytoine, mephenytoin, ethosuximide,methsuccimide, clonazepam, clorazepate, diazepam, carbamazepine,valproic acid, gabapentin, topiramate, felbamate, and phenobarbital. 46.A process for the conversion of at least one active pharmaceuticalingredient into a tannate salt complex for incorporation into atherapeutic tablet, capsule or other solid dosage form, the processcomprising mixing the salt or free base of the at least one activepharmaceutical ingredient, tannic acid, and a dispersing agent in apharmaceutically acceptable liquid to form a tannate salt complex of theat least one pharmaceutical active ingredient for incorporating into atablet, capsule or other dosage form; wherein the at least onepharmaceutical active ingredient is selected from the group consistingof an antinausea agent, an antiemetic, a sedative and an anticonvulsiveand wherein the antinausea agent is selected from the group consistingof: doxylamine, proclorperazine, promethazine HCl, metochlopromide HCl,trimethobenzamide HCl, and ondansetron HCl.
 47. The process of claim 46further comprising incorporating the tannate salt complex of the atleast one pharmaceutical active ingredient into a tablet, capsule, orother dosage form.
 48. The process according to claim 46 wherein thedispersing agent is selected from the group consisting of naturalmagnesium aluminum silicate and synthetic magnesium aluminum silicate.49. The process according to claim 48 wherein the dispersing agent issynthetic magnesium aluminum silicate.
 50. The process according toclaim 46 further comprising adding a non-tannate active pharmaceuticalingredient.
 51. (canceled)
 52. (canceled)
 53. The process according toclaim 46 wherein the antiemetic is selected from the group consistingof: promethazine, cyclizine, diphenhydramine, meclizine, chlorpromazine,droperidol, hydroxyzine, metoclopramide, proclorperazine,trimethobenzamide, cisapride, h2-receptor antagonists, and ondansetron.54. The process according to claim 46 wherein the sedative is selectedfrom the group consisting of: clorazepate, diazepam, estazolam,flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam,triazolam, quazepam, zolpidem, zaleplon, amitriptyline, trimipramine,and trazodone.
 55. (canceled)
 56. The process according to claim 46wherein the anticonvulsive agent is selected from the group consistingof: phenytoine, mephenytoin, ethosuximide, methsuccimide, clonazepam,clorazepate, diazepam, carbamazepine, valproic acid, gabapentin,topiramate, felbamate, and phenobarbital.